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WO2010081778A1 - Bloqueurs de parp pour la prévention et le traitement d'un cancer gastrique induit par helicobacter pylori - Google Patents

Bloqueurs de parp pour la prévention et le traitement d'un cancer gastrique induit par helicobacter pylori Download PDF

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Publication number
WO2010081778A1
WO2010081778A1 PCT/EP2010/050194 EP2010050194W WO2010081778A1 WO 2010081778 A1 WO2010081778 A1 WO 2010081778A1 EP 2010050194 W EP2010050194 W EP 2010050194W WO 2010081778 A1 WO2010081778 A1 WO 2010081778A1
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WIPO (PCT)
Prior art keywords
parp
treatment
gastric cancer
helicobacter pylori
induced gastric
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Ceased
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PCT/EP2010/050194
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English (en)
Inventor
Michael O. Hottiger
Anne Müller
Matthias Altmeyer
Isabella Toller
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Zurich Universitaet Institut fuer Medizinische Virologie
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Zurich Universitaet Institut fuer Medizinische Virologie
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00—Screening for compounds of potential therapeutic value

Definitions

  • This invention relates to the prevention and treatment of Helicobacter pylori induced gastric cancer using blockers of Poly (ADP-ribose) Polymerase (PARP).
  • PARP Poly (ADP-ribose) Polymerase
  • PARPs Poly(ADP-ribose) polymerases
  • PARP1 was the first protein described to catalyze PAR formation.
  • PARP1 was the first protein described to catalyze PAR formation.
  • PARP inhibitors Since the early benzamide inhibitors of the 1980s PARP inhibitors, novel compounds have been developed through structure-activity relationships and crystal structure-based drug design, that are 1 ,000 x more potent. These novel PARP inhibitors have been shown to enhance the antitumour activity of temozolomide (a DNA-methylating agent), topoisomerase poisons and ionising radiation in advanced pre-clinical studies. There are currently at least five PARP inhibitors in clinical trial development. Recent in vitro and in vivo evidence suggests that PARP inhibitors could be used not only as chemo/radiotherapy sensitizers, but as single agents to selectively kill cancers defective in DNA repair, specifically cancers with mutations in the breast cancer associated (BRCA) 1 and 2 genes.
  • BRCA breast cancer associated
  • the present invention relates to a method of preventing and treating Helicobacter pylori induced gastric cancer comprising administering a PARP blocker, and the use of such blockers in said prevention and treatment and in the manufacture of medicaments for preventing and treating Helicobacter pylori induced gastric cancer.
  • the invention further relates to a method of screening for a compound effective in the prevention and treatment of Helicobacter pylori induced gastric cancer comprising contacting a candidate compound with a PARP, and choosing candidate compounds which selectively reduce the activity of PARP.
  • the invention further relates to compounds selected by these methods of screening.
  • Fig. 1 Inhibition of Helicobacter-/nc/ucec/ gastric preneoplastic changes by oral administration of the PARP inhibitor PJ34.
  • lnterleukin-10-deficient mice were infected for 4 weeks with Helicobacter felis, and treated with the PARP inhibitor PJ34 (30mg/kg per day, administered in the drinking water) for either the last 2 or all 4 weeks of the experiment (5 mice in each group) or left untreated (5 mice).
  • Gastric paraffin sections were Giemsa-stained (representative fields are shown in A) and scored with respect to the degree of chronic inflammation as well as the development of atrophy, intestinal metaplasia and compensatory pit cell hyperplasia (B). The quantitative assessment of these four parameters is shown on a scale of 0-6 for all 15 animals included in the study. The median of every group is indicated by a bar. The significance analysis was done using the Mann-Whitney test.
  • Fig. 2 Reversal of Helicobacter -induced gastric preneoplastic changes by oral administration of the PARP inhibitor PJ34.
  • GD4 ⁇ ' ⁇ mice were infected for 4 months with Helicobacter felis, and treated with the PARP inhibitor PJ34 (30mg/kg per day, administered in the drinking water) for the last 4 weeks of the experiment (5 mice per group) or were left untreated (8 mice). Three additional mice remained uninfected and either received PJ34 for the last 4 weeks or not. Giemsa-stained sections from every stomach were processed and the data are displayed as described for Figure 1 . Representative sections are shown in A, and a comprehensive quantitative histopathological analysis is given in B.
  • Fig. 3 Stable reversal of Helicobacter-/nc/ucec/ gastric preneoplastic changes by oral administration of the PARP inhibitor PJ34 in combination with antibiotic eradication therapy.
  • Myd88 v' mice were infected for 3 months with Helicobacter felis, and were either treated with the PARP inhibitor PJ34 (30mg/kg per day, administered in the drinking water) for the second month of the experiment (5 mice per group) or were left untreated (6 mice). Five additional mice further received eradication therapy targeting the infection during weeks 5 and 6 of the experiment.
  • This treatment consisted of metronidazole and tetracycline along with bismuth, and its efficacy was confirmed in a separate independent group (not shown) just after the end of the treatment.
  • mice received only the eradication therapy, and no PJ34. Giemsa-stained sections from every stomach were processed and the data are displayed as described for Figure 1 . Representative sections are shown in A, and a comprehensive quantitative histopathological analysis is given in B.
  • the present invention relates to a method of preventing and treating Helicobacter pylori induced gastric cancer comprising administering a PARP blocker, and the use of such blockers in said prevention and treatment and in the manufacture of medicaments for preventing and treating Helicobacter pylori induced gastric cancer.
  • the present invention is particularly useful for the prevention of Helicobacter pylori induced gastric cancer, because the administration of a PARP blocker inhibits the formation and leads to the regression of infection-induced gastric preneoplastic lesions, such as atrophy, epithelial hyperplasia, and intestinal metaplasia.
  • PARP blockers are compounds which reduce the enzyme activity of PARPs, e.g. PAR formation by PARP-1 , PARP-2 and with reduced sensitivity also PARP10 or inhibit the production, expression or protein stability of PARP or the activation of PARP from its latent form (e.g. intramolecular domain interactions or inhibition of dimer formation), or inhibit binding of PARP to DNA.
  • compounds which inhibit PARP enzyme activity bind to a DNA binding site of PARP or bind to a catalytic domain of PARP.
  • PARP production can be inhibited by anti- sense oligodeoxynucleotides, siRNAs or shRNAs to the different PARP isoforms.
  • Gene therapy can make use of vectors harboring cDNA, which encode for proteins encoding for PARP or for genes involved in the activation or inactivation of PARP.
  • PARP blockers of the invention may belong to the class of inorganic compounds or organic compounds, and are e.g. polypeptides or small organic compounds, preferably derived from templates for the design of novel PARP inhibitors as described in P. Jagtap and C. Szabo, Poly(ADP-Ribose) Polymerase and the therapeutic effect of its inhibitors, Nature Reviews 4, May 2005, 421 -440.
  • PARP blockers are widely known. PARP blockers are, for example, disclosed in P. Jagtap and C. Szabo, Poly(ADP-Ribose) Polymerase and the therapeutic effect of its inhibitors, Nature Reviews 4, May 2005, 421 -440 and in Patent Applications WO 05/097750, WO 05/123687, WO 2006/039545, WO 06/003146, WO 06/003148, and WO 06/003150, which are incorporated herewith by reference. However, the invention is not restricted to the PARP blockers disclosed therein, but extends to all PARP blockers.
  • Preferred PARP blockers according to the invention are (e.g. disclosed in P. Jagtap and C. Szabo, Poly(ADP-Ribose) Polymerase and the therapeutic effect of its inhibitors, Nature Reviews 4, May 2005, 421 -440):
  • AntiPARP 1 and AntiPARP 2 (Octamer, Inc.) - Antibodies that bind to PARP, antigen binding fragments of an antibody (e.g. Fab fragments) or antibody-like molecules (e.g. repeat proteins) which by binding to PARP block its action or block the formation of dimers
  • Antisense molecules for downregulation of PARP are 12-50 nucleotides in length and encode a given sequence found in the exons or introns of PARP genes. Moreover, antisense molecules containing a sequence of the PARP gene promoters and binding within the promoter region may be used. Finally, antisense molecules binding in the 3' UTR -non translated regions of the PARP genes are contemplated
  • PARP blockers are:
  • INO- 1001 INO- 1002 and INO-1003 (Inotek); - AG140699 (Pfizer) - ABT472 and ABT888 (Abott Laboratories)
  • One aspect of the invention relates to a method of preventing and treating Helicobacter pylori induced gastric cancer comprising administering PARP blockers as defined hereinbefore in a quantity effective against Helicobacter pylori induced gastric cancer or the gastric pre-cancerous lesions to a mammal in need thereof, for example to a human requiring such treatment.
  • the treatment may be for prophylactic or therapeutic purposes.
  • the PARP blocker is preferably in the form of a pharmaceutical preparation comprising the PARP blocker in chemically pure form and optionally a pharmaceutically acceptable carrier and optionally adjuvants.
  • the PARP blocker is used in an amount effective against Helicobacter pylori induced gastric cancer or the gastric pre-cancerous lesions.
  • the dosage of the active ingredient depends upon the species, its age, weight, and individual condition, the individual pharmacokinetic data, the mode of administration, and whether the administration is for prophylactic or therapeutic purposes.
  • the daily dose administered is from approximately 0.1 mg to approximately 5000 mg, preferably from approximately 1 mg to approximately 1000 mg, of a PARP blocker.
  • compositions for enteral administration such as nasal, buccal, rectal or, especially, oral administration, and for parenteral administration, such as subcutaneous, intravenous, intramuscular or injections into the cerebrospinal fluid (CSF) compartment are especially preferred.
  • the pharmaceutical compositions comprise from approximately 1 % to approximately 95% active ingredient, preferably from approximately 20% to approximately 90% active ingredient.
  • compositions of the PARP blockers may be sterilized and/or may comprise excipients, for example preservatives, stabilizers, wetting agents and/or emulsifiers, solubilizers, viscosity-increasing agents, salts for regulating osmotic pressure and/or buffers and are prepared in a manner known per se, for example by means of conventional dissolving and lyophilizing processes.
  • suitable carriers are especially fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, and also binders, such as starches, cellulose derivatives and/or polyvinylpyrrolidone, and/or, if desired, disintegrators, flow conditioners and lubricants, for example stearic acid or salts thereof and/or polyethylene glycol.
  • Tablet cores can be provided with suitable, optionally enteric, coatings. Dyes or pigments may be added to the tablets or tablet coatings, for example for identification purposes or to indicate different doses of active ingredient.
  • compositions for oral administration also include hard capsules consisting of gelatin, and also soft, sealed capsules consisting of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the capsules may contain the active ingredient in the form of granules, or dissolved or suspended in suitable liquid excipients, such as in oils.
  • Transdermal application is also considered, for example using a transdermal patch, which allows administration over an extended period of time, e.g. from one to twenty days.
  • Another aspect of the invention relates to the use of PARP blockers as described hereinbefore in the prevention and treatment of Helicobacter pylori induced gastric cancer and in the manufacture of medicaments for the preventing or treating these diseases.
  • medicaments are manufactured by methods known in the art, especially by conventional mixing, coating, granulating, dissolving or lyophilizing.
  • the PARP blocker can be administered alone or in combination with one or more other therapeutic agents, possible combination therapy taking the form of fixed combinations of a PARP blocker and one or more other therapeutic agents known in the prevention or treatment of Helicobacter pylori induced gastric cancer, the administration being staggered or given independently of one another, or being in the form of a fixed combination.
  • Possible combination partners considered are compounds effective against Helicobacter pylori infections, for example proton pump inhibitors and antibiotics.
  • the invention further relates to a method of screening for a compound effective in the prevention or treatment of Helicobacter pylori induced gastric cancer comprising contacting a candidate compound with a PARP and choosing candidate compounds which selectively reduce the activity of PARP.
  • the invention further relates to compounds selected by these methods of screening.
  • Inhibitors of PARP activity are identified by contacting a PARP with a candidate compound.
  • a control assay with the corresponding PARP - in the absence of the candidate compound - is run in parallel.
  • a decrease in activity in the presence of the candidate compound compared to the level in the absence of the compound indicates that the compound is a PARP inhibitor.
  • Screening systems to be used for identification of candidate compounds comprise the following: To measure PAR formation, different PARPs can be incubated for different time periods with 400 ⁇ M tritium labeled NAD and the reaction products are precipitated by TCA before they are analyzed using a beta-counter. Increasing PAR levels synthesized by PARPs can also be detected in a time- and DNA-dependent manner by western blot and vacuum slot blot using anti-PARPs or anti-PAR (e.g. LP96-10) antibodies. PAR formation can alternatively be detected by a pronounced shift of the coomassie-blue stained proteins in the denaturing gel due to a severly reduced migration velocity of the modified proteins when compared to unmodified. Finally, analysis of PAR formation can be verified by silver staining after separation of PAR products with a modified DNA sequencing gel electrophoresis.
  • the findings in three different preclinical models of /-/e/Zcotacter-infection induced gastric cancer indicate that (1 ) oral administration of a PARP inhibitor (e.g. PJ34, 30 mg/kg body weight daily dose, dissolved in the drinking water) efficiently blocks the formation of preneoplastic lesions such as atrophic gastritis, epithelial hyperplasia and intestinal metaplasia. (2) The same treatment further leads to the regression of pre-existing lesions, a finding particularly promising as other treatments for these conditions are currently not available. (3) PARP inhibition induces stable regression of preneoplastic lesions (well beyond the end of therapy) if applied together with antibiotic eradication therapy targeting the Helicobacter infection.
  • a PARP inhibitor e.g. PJ34, 30 mg/kg body weight daily dose, dissolved in the drinking water
  • PARP inhibition blocks the formation of Helicobacter-induced gastric preneoplastic lesions.
  • the C57BI6 mouse represents an excellent model for studying gastric preneoplasia. Wild type mice of this background that are infected with the close H. pylori relative H. felis develop precancerous lesions within 2-3 months of infection. The process is accelerated further in C57BI6 mice lacking the anti-inflammatory cytokine IL-10. These mice are characterized by an excessive, uncontrolled inflammatory and adaptive immune response to the infection. In this strain, atrophic, hyperplastic lesions appear as early as 2-3 weeks post infection. It was chosen to assess the effects of PARP inhibition in this model because it is fast, reproducible and consistent.
  • mice were either infected for 4 months, or were infected and treated with the PJ34 compound (at 30 mg/kg daily dose) for the last month of infection or remained uninfected with or without the compound.
  • An additional infected control group was sacrificed after 3 months (just before the beginning of the PJ34 treatment of the respective study group), which confirmed the formation of preneoplastic lesions at this time (data not shown).
  • the infected group that had not received PJ34 showed a high degree of pathology, with atrophic gastritis, hyperplasia and metaplasia readily detectable in all mice ( Figure 2A and B).
  • mice Infection of Myd88 v' mice typically results in complete atrophy and consistent development of metaplasia in all mice infected for more than 1 month.
  • groups of mice were infected for 3 months (8 mice), or were infected and received PJ34 treatment for the second of the 3 months (8 mice).
  • PJ34 treatment for the second of the 3 months (8 mice).
  • a small subset of each group (2 and 3 mice, respectively) was sacrificed just after the termination of PJ34 treatment at 2 months post infection.
  • mice were maintained for another month without PJ34.

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  • Animal Behavior & Ethology (AREA)
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  • Pharmacology & Pharmacy (AREA)
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Abstract

La présente invention porte sur la prévention et le traitement d'un cancer gastrique induit par Helicobacter pylori, consistant à administrer un bloqueur de la poly(ADP-ribose)polymérase (PARP), et sur l'utilisation de tels bloqueurs pour ladite prévention et ledit traitement, ainsi que pour la fabrication de médicaments destinés à prévenir et traiter un cancer gastrique induit par Helicobacter pylori.
PCT/EP2010/050194 2009-01-17 2010-01-11 Bloqueurs de parp pour la prévention et le traitement d'un cancer gastrique induit par helicobacter pylori Ceased WO2010081778A1 (fr)

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EP09000636 2009-01-17
EP09000636.2 2009-01-17

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WO2005097750A1 (fr) 2004-03-30 2005-10-20 Aventis Pharmaceuticals Inc. Pyridones substitues inhibiteurs de la poly(adp-ribose) polymerase (parp)
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WO2009051815A1 (fr) * 2007-10-19 2009-04-23 Bipar Sciences, Inc. Procédés et compositions pour le traitement du cancer au moyen d'inhibiteurs de parp de type benzopyrone
WO2009114459A2 (fr) * 2008-03-10 2009-09-17 The Trustees Of The University Of Pennsylvania Régime thérapeutique antinéoplasique combiné comprenant la co-disruption de la voie parp et du complexe mre11/rad50/nbs1, et compositions utiles à cette fin

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